Trisomy 21, the chromosome abnormality associated with over 95% of Down syndrome (DS), is the most important genetic cause of mental retardation, with an estimated incidence of 1/600 livebirths. Despite its high rate of occurrence and obvious clinical importance, we still know surprisingly little about the mechanism of origin of trisomy 21 or about factors which may predispose to non-disjunction of chromosome 21. In the proposed studies, we intend to combine cytogenetic, molecular and epidemiological approaches to address these questions. In one set of investigations we will focus on the genesis of trisomy 21, conducting studies to determine the effect of aberrant recombination and paternal non-disjunction, with particular emphasis on examining the association between maternal age and trisomy 21. In companion studies, we will investigates the hypothesis that specific environmental exposures may influence the frequency of trisomy 21, and confirm or refute preliminary observations that two such factors-smoking and oral contraceptive use-are risk factors for trisomy 21.